CN101804064B - Application of dihydroquercetin and glucoside compounds to preparing drug-resistance bacteria medicine - Google Patents
Application of dihydroquercetin and glucoside compounds to preparing drug-resistance bacteria medicine Download PDFInfo
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Abstract
The invention discloses application of dihydroquercetin and glucoside compounds to preparing a medicine for resisting drug-fast bacteria. With the invention, the dihydroquercetin and glucoside compounds can be extracted from decogenus plants, such as Hypericum Japonicum Thunb, and the activity of the dihydroquercetin and glucoside compounds for resisting the drug-fast bacteria can be proved; proved by a pharmacological experiment, the dihydroquercetin and glucoside compounds not only have remarkable direct inhibition function on common-clinically meticillin-resistant staphylococcus aureus (MRSA), but also can enhance the action of the traditional antibiotic for resisting the drug-fast bacteria. The dihydroquercetin and glucoside compounds can be further used as active components and used for preparing a medicine for treating the drug-fast bacteria infection; and preparation forms includes oral preparations, injections and/or external preparations which are prepared by combining with acceptable carriers.
Description
Technical field
The present invention relates to the flavanone alcohol compound, especially dihydroquercetin and glucosides class thereof the new purposes in preparation methicillin-resistant staphylococcus aureus resistance medicine.
Background technology
Along with antibiotic extensive use, increasing antibacterial produces drug resistance to common antibiotics, and drug-resistant intensity increases the weight of day by day.Since Britain in 1961 at first reports methicillin-resistant staphylococcus aureus MRSA (Methicillin-resistantStaphylococcus aureus); So far find in succession all over the world; And MRSA infects in rising trend, even causes eruption and prevalence in the hospital.MRSA and AIDS, hepatitis, cancer are listed as the big pertinacious disease in four in the world today at present.MRSA is to multiple antibiotics resistance, and pathogenicity is strong and therapeutic effect is poor, for causing one of The main pathogenic fungi of hospital infection.Because its multi-drug resistant; Promptly except to a few antibiotic such as vancomycin effectively; Almost to having all drug resistances of antibiotic such as all kinds of antibiotic such as beta-lactam, FQNS, Macrolide, aminoglycoside now; And infect pilosity and be born in immunodeficiency person, the old and the weak patient and burn, patient with operation, so the treatment difficulty is big, case fatality rate is high, causes medical personnel's great attention.Since the establishment of the nation; Though China carried out screening study to the effect of infection such as the anti-golden Portugal of Chinese herbal medicine bacterium; But these researchs are limited to medicinal substances extract more, and the effect of fastbacteria is also just just obtained paying close attention in recent years, and the research of the domestic rare so far monomeric compound that infects to MRSA is reported.We are directed against clinically the present situation of drug-fast bacteria infection both at home and abroad; Concentrate Yunnan product medicinal plants is comprised that the anti-MRSA flavones ingredient in the Herba Hyperici Japonici has carried out going deep into screening study; Having found first has the flavanone alcohol compound than strong inhibitory activity to MRSA; Discover that further this compounds can also make MRSA that existing antibiotic is played sensitization, particularly can strengthen even reverse the anti-MRSA effect to the invalid fluoroquinolone antibiotics of MRSA.
Dihydroquercetin and glucoside compound thereof belong to the flavanone alcohol compound; The inventor retrieves the following patent of the relevant anti-MRSA of this compounds both at home and abroad: patent documentation 1; US 6294526B1, Use of flavone derivatives forinduction of β-lactam-sensitivity of MRSA; Patent documentation 2, US 2006/0229262A1, Pharmaceuticalcomposition for treatment of infection with drug resistant bacterium and disinfectant.The flavanone alcohol compound Taxifolin of wherein mentioning (Taxifolin) has another name called dihydroquercetin (Dihydroquercetin) and has anti-MRSA effect, and can strengthen the anti-MRSA effect of methicillin beta-lactam antibiotics such as (Methicillin).The inventor also retrieves dihydroquercetin derivant (2R; 3R)-dihydroquercetin-7; 4 '-dimethyl ether has anti-dermatophyte effect (Pacciaroni Adel V et al; Antifungal activity of Heterothalamus alienus metabolites.Phytother Res.2008; 22:524-528) and astilbin or Taxifolin-3-rhamnoside (Astilbin taxifolin-3-rhamnoside) has the effect of anti-skin microorganism species, wherein; To the staphylococcic minimum amount of suppression of epidermis (minimal inhibitory quantity; MIQ) be 50 μ g (Moulari B et al.Isolation and in vitro antibacterial activity of astilbin, thebioactive flavanone from the leaves of Harungana madagascariensis Lam.ex Poir. (Hypericaceae) .J.Ethnopharmacol.2006,106:272-278).
Take a broad view of the report of domestic and international patent and other documents, the Taxifolin effect of in above-mentioned patent documentation, mentioning, do not have a patent or other documents to refer in particular to the anti-MRSA effect of dihydroquercetin involved in the present invention and glucoside compound thereof.
Summary of the invention
The new purposes that the purpose of this invention is to provide the anti-MRSA of application, especially chemical compound Taxifolin (I) in preparation antimicrobial agent MRSA medicine of dihydroquercetin and glucoside compound thereof, astilbin (II), Taxifolin-7-rhamnoside (III).
The present invention is based on the reality that current clinical drug-resistant bacterium infects; In conjunction with antibiotic medicine sensitivity screening of plant amedica and effective ingredient isolation and purification method, from Guttiferae (Guttiferae) Herba Hyperici Japonici medicinal plants such as (Hypericumjaponicum Thunb.), extract dihydroquercetin and glucoside compound thereof and confirm that its antimicrobial agent is active.
Active dihydroquercetin of the present invention and glucoside compound thereof have the chemical constitution of following formula I~III representative:
R
1 R
2
I Taxifolin (Taxifolin) H H
II Taxifolin-3-rhamnoside (astilbin) rha H
(Taxifolin-3-O-α-L-rhamnoside,Astilbin)
III Taxifolin-7-rhamnoside H rha
(Taxifolin-7-O-α-L-rhamnoside)
Wherein, rha is the abbreviated form of rhamanopyranosyl (rhamnosyl).R
1And R
2Be hydroxyl, polyhydroxy compounds such as monosaccharide (rhamnose, glucose, arabinose, xylose and fructose etc.), substituted monosaccharide and polymer thereof with 2~6 carbon atoms.
Above-claimed cpd and the derivant purposes in the preparation drug-resistance bacteria medicine; Comprise directly to the fastbacteria antibacterial action of (containing non-fastbacteria); And during with the antibiotic Combined application; Have antibiotic sensitization, promptly can strengthen antibiotic curative effect even reversing drug resistance bacterium for antibiotic drug resistance.
Fastbacteria is meant methicillin-resistant staphylococcus aureus; Non-fastbacteria is meant staphylococcus aureus.
Chemical compound is meant compound I I and III, and said antibiotic classification by enhanced sensitivity comprises that beta-lactam and FQNS antibiosis even reversing drug resistance bacterium are for antibiotic drug resistance.
Fastbacteria is meant methicillin-resistant staphylococcus aureus; Non-fastbacteria is meant staphylococcus aureus.
Chemical compound is meant compound I I and III, and said antibiotic classification by enhanced sensitivity comprises beta-lactam and fluoroquinolone antibiotics; Perhaps, be meant fluoroquinolone antibiotics by the antibiotic classification of enhanced sensitivity.
Described dihydroquercetin and glucoside compound thereof are through pharmacological testing; The result confirms except common clinically methicillin-resistant staphylococcus aureus (MRSA) is had the significant direct repression; Can also strengthen existing antibiotic antimicrobial agent effect; Chemical compound dihydroquercetin of the present invention and glucoside compound thereof can be processed the medicine of novel therapeutic drug-fast bacteria infection further as active component.Dosage form comprises oral formulations, injection and/or the external preparation of processing with the drug acceptable carrier combination.
Structure of the dihydroquercetin that the present invention relates to and glucoside compound I~III thereof and preparation method thereof is published in document.In multiple medicinal plants monoid, distribution is arranged all as one or more among the compound I~III of effective ingredient in the present invention, surplus Guttiferae (Guttiferae), pulse family (Leguminosae), Labiatae (labiateae), Cactaceae (Cactaceae), Winteraceae (Illiciaceae), Polygonaceae (Polygonaceae), Salicaceae (Salicaceae), Ericaceae (Ericaceae), Dilleniaceae (Dilleniaceae), Cunoniaceae (Eucryphiaceae), coniferale (Coniferae), Hamamelidaceae (Hamamelidaceae), Balanophoraceae (Balanophoraceae), Lauraceae (Lauraceae), Sapotaceae (Sapotaceae), Anacardiaceae (Anacardiaceae), Fagaceae (Fagaceae), Rosaceae (Rosaceae) etc. 20, in the section plant distribution is arranged all like Taxifolin.Ishiguro etc. once separated from Herba Hyperici Japonici (Hypericum japonicum) and obtained Taxifolin-7-rhamnoside (Ishiguro K.; Et al.A flavanonol rhamnoside from Hypericum japonicum.Photochemistry; 1991,30 (9): 3152).
The dihydroquercetin and the glucoside compound thereof that are used for embodiment of the present invention can be by the extraction separation method preparations of document prompting, and wherein Taxifolin (I) and astilbin (II) also can obtain through commercially available approach.Illustrative compound III can make from Herba Hyperici Japonici (Hypericum japonicum Thunb.).But these enforcements only provide with way of example, and do not play the qualification effect.
The explanation of subordinate list:
Table 1 is the drug sensitive test result of MRSA strains;
Table 2 is that flavanone alcohol compound I~III and four kinds of antibiotic lists are used the MIC to MSSA and 10 strain MRSA;
Table 3 are Taxifolin-7-rhamnosides (III) with four kinds of antibiotic to 10 strain MRSA drug combination MIC and FIC indexes;
Table 4 is astilbin (II) and the anti-MRSA effect of combined with levofloxacin;
Table 5 is Taxifolin (I) and the anti-MRSA effect of combined with levofloxacin;
Table 6 is that agar diffusion method of the paper records Taxifolin-7-rhamnoside (III) to the inhibition zone of MRSA4 to three kinds of fluoroquinolone antibiotics.
The specific embodiment
Embodiment 1: extraction separation monomer Taxifolin from the Herba Hyperici Japonici herb-7-rhamnoside (III)
Get the dry herb coarse powder 4.76kg of Herba Hyperici Japonici (Hypericumjaponicum Thunb Murray) and under room temperature, flooded 7 days, filter, repeat 3 times with 80% ethanol 23L.Extracting solution merges, and concentrating under reduced pressure gets extractum 505g.Extractum processed behind the suspension with distilled water distribute extraction with petroleum ether, ethyl acetate, n-butyl alcohol successively.Obtain 90g respectively after each organic layer evaporated under reduced pressure, 160g, 105g extractum, surplus is the water position.Get ethyl acetate layer extractum 90g with silicagel column (200-300 order; 2kg), with ethyl acetate-methanol (1: 0-0: 1) be the eluant gradient elution, wherein 5% methanol-eluted fractions position (8g) reuse silicagel column (300-400 order; Be the eluant gradient elution 300g) with petroleum ether-ethyl acetate-methanol (3: 1: 0.2-2: 2: 1); 3: 1: 0.2 the solvent elution position (0.6g) carry out low pressure silica gel column chromatography and polydextran gel Sephadex LH-20 column chromatography, through thin layer chromatography inspection, contain same composition person and merge; Obtain chemical compound Taxifolin-7-rhamnoside (III, 150mg).
Embodiment 2: the physics and chemistry and the spectral data of Taxifolin-7-rhamnoside (III)
Yellow powder (methanol), C
21H
23O
11 +, mp 150-153 ℃.ESI?MS(positive?ion?mode)m/z:451。
1HNMR(CD
3OD,400MHz):δ
H6.97(1H,s,J=11.6Hz,H-2′),6.83(1H,dd,J=1.0,8.0Hz,H-6′),6.79(1H,d,J=8.1Hz,H-5′),6.26(1H,d,J=1.9Hz,H-8),6.17(1H,d,J=1.8Hz?H-6),5.47(1H,d,J=5.4Hz,H-1),4.95(1H,d,J=11.6Hz,H-2),4.56(H,d,J=11.6Hz,H-3),3.96(1H,s,Rha-H-2),3.76(H,dd,J=3.1,9.4Hz,Rha-H-3),3.53(1H,m,Rha-H-5),3.43(1H,t,Rha-H-4),1.22(3H,d,J=6.0Hz?Rha-Me);
13C?NMR(CD
3OD,100MHz):δ
C?115.9(d,C-2),73.8(s,C-3),199.3(s,C-4),164.9(s,C-5),98.0(d,C-6),166.2(s,C-7),96.9(d,C-8),164.2(s,C-9),103.4(s,C-10),129.6(s,C-1′),115.9(d,C-2′),146.3(s,C-3″),147.2(s,C-4′),116.1(d,C-5′),120.9(d,C-6′),99.6(d,C-1″),71.6(d,C-2″),72.0(d,C-3″),73.6(d,C-4″),71.2(d,C-5″),18.0(d,C-6″)。
Embodiment 3: be used as the screening of the clinical drug-resistant bacterial strain MRSA of drug sensitive test
1. test material
Antibiotics drug sensitive test paper (Nat'l Pharmaceutical & Biological Products Control Institute), MH agar (sky, Hangzhou and microorganism reagent company limited).
2. BIAO and BEN is originated
Separation screening 10 strain antibacterials are numbered MRSA189, MRSA155, MRSA328, MRSA144, MRSA247, MRSA4, MRSA92, MRSA55, MRSA330, MRSA123 from applicant's clinical samples, and refrigerator-20 ℃ following preservation is subsequent use.
3. antibacterial is differentiated
According to " national Clinical Laboratory rule of operation " and well known to a person skilled in the art that the antibacterial discrimination method separates, cultivates above-mentioned BIAO and BEN antibacterial; Through being accredited as staphylococcus aureus (SA); And by known antibiotics susceptibility conventionally test method (K-B paper disk method); Carry out fastbacteria with reference to U.S. clinical laboratory standard committee (NCCLS) standard in 2004 and identify, cefoxitin to the inhibition zone of all bacterial strains all≤19mm, so be regarded as drug resistance SA bacterial strain (MRSA).
4. drug sensitive test
Further use the K-B paper disk method; According to China's Ministry of Public Health in " the paper disk method antibacterials STT standard " of on May 1st, 2000 issuing and implementation (SAST) routine operation; In 35 ℃ of cultivations 17 hours, measure the sensitivity of 10 strain MRSA to antibiotics commonly used with the MH agar culture medium, the result sees table 1.
The drug sensitive test result of table 1.MRSA strains
Bacterial strain | Drug resistance | Intermediary | Responsive |
?MRSA189 | Penicillin, ampicillin, oxazacillin, cefoxitin, cefazolin sodium, cefuroxime, rifamycin | / | Vancomycin, MOXIFLOXACIN, celestial, the sharp naphthalene azoles amine of federal his azoles |
?MRSA155 | Penicillin, cefazolin sodium, cefuroxime, cefoxitin, azithromycin, clarithromycin, clindamycin | / | Vancomycin, Gatifloxacin, sharp naphthalene azoles amine |
?MRSA328 | Penicillin, ampicillin, oxazacillin, clarithromycin, clindamycin, cefuroxime, cefazolin sodium, azithromycin | Levofloxacin | Vancomycin, federal his azoles celestial being, fosfomycin, sharp naphthalene azoles amine |
?MRSA144 | Penicillin, oxazacillin, ampicillin, azithromycin, clindamycin, clarithromycin, cefazolin sodium, cephalo sulfur miaow, cefuroxime | / | Vancomycin, fosfomycin, sharp naphthalene azoles amine |
?MRSA247 | Penicillin, oxazacillin, ampicillin, azithromycin, cefazolin sodium, cephalo sulfur miaow, cefuroxime | Clindamycin | Vancomycin, fosfomycin, sharp naphthalene azoles amine |
?MRSA4 | Penicillin, oxazacillin, ampicillin, azithromycin, cefazolin sodium, cephalo sulfur miaow, cefuroxime | Gatifloxacin | Vancomycin, federal his azoles celestial being, fosfomycin, sharp naphthalene azoles amine |
?MRSA92 | Penicillin, oxazacillin, ampicillin, azithromycin, cefazolin sodium, cephalo sulfur miaow, cefuroxime, levofloxacin | / | Vancomycin, Gatifloxacin, federal his azoles celestial being, fosfomycin, sharp naphthalene azoles amine |
?MRSA55 | Oxazacillin, ammonia benzyl two woodss, azithromycin, clindamycin, penicillin, clarithromycin, erythromycin, cefazolin sodium, cephalo sulfur miaow, cefuroxime | Gatifloxacin | Vancomycin, fosfomycin, sharp naphthalene azoles amine |
?MRSA330 | Penicillin, ampicillin, oxazacillin, cefazolin sodium, cefuroxime, levofloxacin, clarithromycin, azithromycin, | Cephalo sulfur azoles | Vancomycin, Gatifloxacin, federal his azoles celestial being, fosfomycin, sharp naphthalene azoles amine |
?MRSA123 | Penicillin, ammonia benzyl two woodss, oxazacillin, cefazolin sodium, cefuroxime, levofloxacin, clarithromycin, azithromycin, | / | Vancomycin, fosfomycin, sharp naphthalene azoles amine |
Embodiment 4: compound I~III measures direct antibacterial activity and the antibiotic sensitization of Resistant strain MRSA
1. test material
Culture medium: MH meat soup (sky, Hangzhou and microorganism reagent company limited); Receive reagent: dihydroquercetin-7-O-rhamnoside (obtaining) ampicillin (North China pharmacy) by extraction separation in the Herba Hyperici Japonici; Ceftazidime (long-pending big pharmacy); Levofloxacin (Yangtze River pharmacy), azithromycin (Yangtze River pharmacy), solvent: DMSO (analytical pure), distilled water; Standard gold Staphylococcus aureus (MSSA): ATCC25923 (Nat'l Pharmaceutical & Biological Products Control Institute), fastbacteria (MRSA): MRSA189, MRSA155, MRSA328, MRSA144, MRSA247, MRSA4, MRSA92, MRSA55, MRSA330, MRSA123:
2. medicinal liquid preparation
Aseptic DMSO is made into 1024 μ g/mL, 2048 μ g/mL, 2048 μ g/mL, 512 μ g/mL, 8192 μ g/mL solution respectively as former drug solns with Taxifolin-7-rhamnoside, ampicillin, ceftazidime, levofloxacin and azithromycin.
Dilution method is measured ampicillin, ceftazidime, levofloxacin, azithromycin, monomer minimum inhibitory concentration value (the Minimal inhibitory concentration to MRSA respectively; MIC); Earlier be made into monomer, levofloxacin respectively the stock solution of 1024 μ g/mL, 128 μ g/mL; Ampicillin, ceftazidime, azithromycin all are made into the stock solution of 2048 μ g/mL, all use dilution method to measure their the M IC to MRSA respectively, and control bacteria suspension concentration is 1.0 * 10
6CFU/mL.
3. the preparation of bacterium liquid
With inoculating loop inoculation on the MH agar plate, place 35 ℃ of calorstats to cultivate 24h, the reuse inoculating loop is transferred to bacterial strain in the test tube, using physiological saline solution to be made into concentration is 1.0 * 10
6CFU/mL controls bacteria suspension.
4. measure the minimal inhibitory concentration (MIC) that medicine suppresses MRSA
Adopt known doubling dilution, get aseptic 96 orifice plates, add 200 μ L MH broth bouillons in No. 1 hole of every horizontally-arranged and make blank, No. 12 holes add the MH broth bouillon and each 100 μ L of bacterium liquid make positive control.Every horizontally-arranged 2-11 hole earlier adds 50 μ L MH broth bouillons, gets original liquid 50 μ L and No. 2 hole mixings, draw 50 μ L then and add in No. 3 holes, and the like be diluted to the o.11 hole, discard 50 μ L, the 2-11 hole each to add all that 100 μ L dilute be 1.0 * 10
6CFU/mL bacterium liquid shakes up, and puts in the incubator in 35 ℃ and cultivates 24 hours, receives reagent thing activity rating by method as well known to those skilled in the art, and gained is measured the result and seen table 2.
Table 2. flavanone alcohol compound I~III and four kinds of antibiotic lists are used the MIC to MSSA and 10 strain MRSA
(unit: μ g/mL)
The antibacterial numbering | MSSA | 189 | 155 | 328 | 144 | 247 | 4 | 92 | 55 | 330 | 123 |
I | / | 512 | 512 | 512 | 512 | 512 | 512 | 512 | 512 | 512 | 512 |
II | / | 512 | 512 | 512 | 512 | 512 | 512 | 512 | 512 | 512 | 512 |
III | 8 | 32 | 64 | 64 | 64 | 32 | 64 | 32 | 64 | 64 | 64 |
AMP | 16 | 64 | 128 | 128 | 64 | 64 | 64 | 16 | 128 | 64 | 64 |
CAZ | 32 | 512 | 512 | 512 | 512 | 512 | 256 | 128 | 512 | 256 | 512 |
LEO | 2 | 16 | 16 | 8 | 8 | 16 | 16 | 8 | 16 | 16 | 16 |
AZI | >1000 | 2048 | 2048 | 2048 | 2048 | 2048 | 2048 | 2048 | 2048 | 2048 | 2048 |
MSSA: MSSA (standard bacterium ATCC25923); AMP, the ampicillin; CAZ, ceftazidime; LEO, levofloxacin; AZI, azithromycin.
5. compound I~III and antibiotic are united bacteriostatic experiment
5.1 checkerboard type micro-dilution method (checkerboard microdilution assay)
Chessboard method can accurately be measured the interaction that two kinds of antibacterials are produced under the ratio of debita spissitudo.Two kinds of medicines that share carry out duple doubling dilution respectively with vertical (A to H) of two-dimentional chessboard horizontal (2-11) two directions on 96 orifice plates, measure the MIC of drug combination.FICI is a major parameter of estimating two medicine interaction modes of the external drug combination of medicine.(Fractional inhibitory concentration FIC) is each medication combined required minimum inhibitory concentration (MIC when antibacterial to part Mlc index
c) MIC with separately the time
aRatio, FICI then equals two kinds of medicine FIC sums.The formula that calculates is: FICI=FIC
1+ FIC
2=MIC
1a/ MIC
1c+ MIC
2a/ MIC
2cWhen FICI≤0.5, be synergism; When 1>=FICI>0.5, be summation action; When 2>=FICI>1, the external interaction mode of medicine is for irrelevant; When FIC index>2, be antagonism.The result sees table 3~5.
Table 3. Taxifolin-7-rhamnoside and four kinds of antibiotic are to 10 strain MRSA drug combination MIC and FIC indexes
aT7R: Taxifolin-7-rhamnoside; AMP, the ampicillin; CAZ, ceftazidime; LEO, levofloxacin; AZI, azithromycin;
bMIC
50, the concentration of inhibition 50%MRSA; MIC
90, the concentration of inhibition 90%MRSA.
FICI
50, the FIC index of inhibition 50%MRSA; FICI
90, the FIC index of inhibition 90%MRSA.
The anti-MRSA effect of table 4 astilbin and combined with levofloxacin (unit: μ g/mL)
The anti-MRSA effect of table 5 Taxifolin and combined with levofloxacin (unit: μ g/mL)
5.2 record Taxifolin-7-rhamnoside to the inhibition zone of MRSA4 to three kinds of fluoroquinolone antibiotics with agar diffusion method of the paper, the result sees table 6.
Table 6 agar diffusion method of the paper records Taxifolin-7-rhamnoside to the inhibition zone of MRSA4 to three kinds of fluoroquinolone antibiotics
aThe amount of drug combination compound III is 64 μ g/ sheets.
Claims (4)
1. dihydroquercetin and glucoside compound thereof are in preparation methicillin-resistant staphylococcus aureus resistance medicine and the purposes that resists in the medicine of anti-the staphylococcus aureus, and said chemical compound has direct antibacterial action to fastbacteria;
When said chemical compound and antibiotic Combined application, have, can strengthen antibiotic drug effect even reverse methicillin-resistant staphylococcus aureus for antibiotic drug resistance to antibiotic sensitization; Said antibiotic classification by enhanced sensitivity comprises beta-lactam and fluoroquinolone antibiotics;
Described dihydroquercetin and glucoside compound thereof have the chemical constitution of following general formula, i.e. compound I, II and III or its officinal salt:
R
1 R
2
I Taxifolin H H
II Taxifolin-3-rhamnoside rha H
III Taxifolin-7-rhamnoside H rha
Wherein, rha is the abbreviated form of rhamanopyranosyl rhamnosyl, R
1And R
2For hydroxyl, polyhydroxy compounds with 2~6 carbon atoms are selected from monosaccharide, substituted monosaccharide and polymer thereof.
2. by the described purposes of claim 1, it is characterized in that described chemical compound is meant compound I I and III, said antibiotic classification by enhanced sensitivity comprises beta-lactam and fluoroquinolone antibiotics.
3. by the described purposes of claim 1, it is characterized in that described chemical compound is meant compound I, II and III, said antibiotic classification by enhanced sensitivity is meant fluoroquinolone antibiotics.
4. by each described purposes of claim 1~3, it is characterized in that said preparation of compositions is a dosage form, said dosage form comprises oral formulations, injection and/or the external preparation of processing with the drug acceptable carrier combination.
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